EP1467744B1 - Aqueous compositions containing metronidazole - Google Patents

Aqueous compositions containing metronidazole Download PDF

Info

Publication number
EP1467744B1
EP1467744B1 EP02778822A EP02778822A EP1467744B1 EP 1467744 B1 EP1467744 B1 EP 1467744B1 EP 02778822 A EP02778822 A EP 02778822A EP 02778822 A EP02778822 A EP 02778822A EP 1467744 B1 EP1467744 B1 EP 1467744B1
Authority
EP
European Patent Office
Prior art keywords
solution
metronidazole
concentration
niacinamide
bcd
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP02778822A
Other languages
German (de)
English (en)
French (fr)
Other versions
EP1467744A2 (en
EP1467744A4 (en
Inventor
Yunik Chang
Gordon J. Dow
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dow Pharmaceutical Sciences Inc
Original Assignee
Dow Pharmaceutical Sciences Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=21872727&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=EP1467744(B1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Dow Pharmaceutical Sciences Inc filed Critical Dow Pharmaceutical Sciences Inc
Priority to EP10170958A priority Critical patent/EP2238980A1/en
Priority to EP10170977A priority patent/EP2241320A1/en
Publication of EP1467744A2 publication Critical patent/EP1467744A2/en
Publication of EP1467744A4 publication Critical patent/EP1467744A4/en
Application granted granted Critical
Publication of EP1467744B1 publication Critical patent/EP1467744B1/en
Priority to CY20101101017T priority patent/CY1111095T1/el
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/724—Cyclodextrins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
    • C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C08J3/075—Macromolecular gels
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/16—Cyclodextrin; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2301/00—Characterised by the use of cellulose, modified cellulose or cellulose derivatives
    • C08J2301/02—Cellulose; Modified cellulose
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
    • C08J2305/16—Cyclodextrin; Derivatives thereof

Definitions

  • the invention pertains to the field of topically applied medications for treatment of skin and mucosal disorders.
  • the invention pertains to aqueous compositions containing metronidazole as the active ingredient.
  • Metronidazole 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole
  • metronidazole has also been shown to be useful in treating various skin disorders, including acne rosacea, bacterial ulcers, and perioral dermatitis.
  • Borgman U.S. Patent No. 4,837,378
  • Metronidazole has been found to have an anti-inflammatory activity when used topically to treat dermatologic disorders. See, Czernielewski, et al., U.S. Patent No. 5,849,776 .
  • Metronidazole may also be used as an intravaginal therapeutic agent for the treatment of bacterial vaginosis. See, Borgman, U.S. Patent No. 5,536,743 .
  • compositions containing metronidazole for treatment of dermatologic disorders are available in cream, lotion and gel forms.
  • One commercially available metronidazole cream product, NORITATETM (Dermik Laboratories, Inc., Collegeville, PA 19426 USA) contains 1% metronidazole in which the insoluble drug is suspended in the opaque cream.
  • a commercially available metronidazole gel product, METROGEL® (Galderma Laboratories, Inc. Fort Worth, Texas, 76133 USA), contains 0.75% metronidazole which is solubilized to produce a clear gel..
  • solubilized water-based formulation such as a gel
  • creams, lotions (typically oil in water emulsions) and ointments are often comedogenic, acnegenic, or not cosmetically appealing to patients.
  • Solubilized topical products are generally more bioavailable than products in which the active ingredient is insoluble.
  • oil-based cream and ointment metronidazole formulations have an advantage over presently available gel-based formulations in that oil-based formulations may contain a concentration of metronidazole of 1%.
  • Aqueous-based gel compositions are limited to a concentration of metronidazole of 0.75% because of the poor solubility of metronidazole in water.
  • Cyclodextrins have been shown to enhance the solubility of various drugs in aqueous solutions.
  • An amphiphilic or lipophilic drug, such as metronidazole, is partially or completely enclosed within this cage structure, thereby increasing the solubility of the drug in aqueous media.
  • Cyclodextrins have certain disadvantages, however, including expense, limitations of cyclodextrin solubility, incompatibility in certain vehicles, and potential for local and systemic toxicity.
  • BCD beta-cyclodextrin
  • cyclodextrins such as BCD and its derivatives
  • BCD drug formulations containing BCD as a solubilizing agent likewise become expensive.
  • Solubility enhancing agents other than cyclodextrins have been described. Yie W. Chien, Journal of Parenteral Science and Technology, 38(1):32-36 (Jan. 1984 ), discloses that niacinamide is a solubility enhancing agent that can increase the water solubility of MTZ. Chien further discloses that the water soluble vitamins ascorbic acid, and pyridoxine are solubility enhancing agents for aqueous solutions. Chien discloses that the solubility of metronidazole in water increases linearly with relation to the concentration of these water soluble vitamins in the solution. The prior art does not address the combination of cyclodextrins, such as BCD, with other solubility enhancing agents, such as niacinamide or other water soluble vitamins.
  • a cyclodextrin and a second solubility enhancing agent such as niacinamide or niacin
  • the second solubility enhancing agent may be other than niacinamide or niacin.
  • the synergistic effect provided by the combination of cyclodextrin and the second solubility enhancing agent permits the use of lower concentrations of cyclodextrins than would be necessary to obtain a desired level of solubility of the chemical compound in the absence of the second solubility enhancing agent.
  • the invention provides an important way to greatly reduce costs in the formulation and preparation of pharmaceutical preparations, as well as to increase the solubilizing capability of cyclodextrins such as BCD, and to obtain desired concentrations of pharmacologic compounds while minimizing the amount of cyclodextrins used.
  • solubility enhancing agent or “solubility enhancer” means a chemical compound that, when present in solution in a solvent, increases the solubility of a second chemical compound, such as an active ingredient, in the solvent, but which chemical compound is not itself a solvent for the second chemical compound.
  • the invention is described below with reference to a particular cyclodextrin, BCD, and a particular chemical compound, metronidazole. It is conceived, however, that the invention is applicable to other cyclodextrins, both crystalline and non-crystalline, including alpha and gamma cyclodextrins, and crystalline and non-crystalline derivatives thereof, and other amphiphilic and lipophilic chemical compounds besides metronidazole.
  • aqueous solutions of higher than 0.75% metronidazole may be obtained by combining in the solution a first solubility enhancing agent which is a cyclodextrin, such as beta-cyclodextrin (BCD), and a second solubility enhancing agent, such as niacinamide or niacin.
  • BCD beta-cyclodextrin
  • BCD beta-cyclodextrin
  • niacinamide or niacin niacinamide
  • the combination of the cyclodextrin and the second solubility enhancing agent provides a synergistic effect in increasing the solubility of MTZ in water.
  • the invention is an aqueous solution having a concentration of MTZ higher than 0.75% w/w, preferably about 1% or higher.
  • the aqueous solution contains a cyclodextrin, such as BCD, as a first solubility enhancing agent and a second solubility enhancing agent, such as niacin or niacinamide.
  • a cyclodextrin such as BCD
  • a second solubility enhancing agent such as niacin or niacinamide.
  • the level of each of the cyclodextrin and the second solubility enhancing agent is less than that which, in the absence of the other solubility enhancing agent, would provide for a dissolved concentration of the MTZ to the level of that present in the aqueous solution.
  • the solution may contain an excess of the second solubility enhancing agent.
  • the enhanced solubility of MTZ in the combination solution is higher than the sum of the enhanced solubilities of MTZ in two solutions, each of which contains a single solubility enhancer at the concentration present in the combination solution.
  • the solution is substantially free of aqueous solubility-enhancing agents other than a cyclodextrin and the second solubility enhancing agent.
  • the solution is an aqueous gel.
  • the invention is a method for the manufacture of an aqueous solution of MTZ having a concentration greater than 0.75%, preferably about 1.0% or higher.
  • the method includes combining MTZ and two solubility enhancing agents, one of which is a cyclodextrin such as BCD, in a water based solution wherein the concentration of the final aqueous solution of MTZ is higher than 0.75%.
  • the level of each of the cyclodextrin and the second solubility enhancing agent is less than that which, in the absence of the other solubility enhancing agent, would provide for a dissolved concentration of the MTZ to the level of that present in the aqueous solution.
  • the enhanced solubility of MTZ in the combination solution is higher than the sum of the enhanced solubilities of MTZ in two solutions, each of which contains a single solubility enhancer at the concentration present in the combination solution.
  • a gelling agent is further combined in the solution, preferably after addition of the MTZ and the solubility-enhancing agents.
  • the invention describes a method for the treatment of a dermatologic or mucosal disorder.
  • the method includes topically applying to affected areas an aqueous solution of MTZ and a cyclodextrin, such as BCD, and a second solubility enhancing agent, such as niacin or niacinamide., which solution has a concentration of MTZ higher than 0.75%, preferably about 1.0% or higher.
  • the level of each of the cyclodextrin and the second solubility enhancing agent is less than that which, in the absence of the other solubility enhancing agent, would provide for a dissolved concentration of the MTZ to the level of that present in the aqueous solution.
  • the solution may contain an excess of the second solubility enhancing agent.
  • the enhanced solubility of MTZ in the combination solution is higher than the sum of the enhanced solubilities of MTZ in two solutions, each of which contains a single solubility enhancer at the concentration present in the combination solution.
  • the aqueous solution is a gel.
  • the invention is a kit for the treatment of a dermatologic or mucosal disorder.
  • the kit of the invention includes a container that contains an aqueous solution of MTZ and which aqueous solution contains a first solubility enhancing agent which is a cyclodextrin, such as BCD, and a second solubility enhancing agent such as niacin or niacinamide.
  • a first solubility enhancing agent which is a cyclodextrin, such as BCD
  • a second solubility enhancing agent such as niacin or niacinamide.
  • the level of each of the cyclodextrin and the second solubility enhancing agent is less than that which, in the absence of the other solubility enhancing agent, would provide for a dissolved concentration of the MTZ to the level of that present in the aqueous solution.
  • the solution may contain an excess of the second solubility enhancing agent.
  • the enhanced solubility of MTZ in the combination solution is higher than the sum of the enhanced solubilities of MTZ in two solutions, each of which contains a single solubility enhancer at the concentration present in the combination solution.
  • the aqueous solution is a gel.
  • aqueous solutions of metronidazole (MTZ) of greater than 0.75% w/w, and even about 1.0% or higher, are able to be obtained by using a combination of solubility-enhancing agents, wherein one of the solubility enhancing agents is a cyclodextrin, such as BCD, and the second solubility enhancing agent is other than a cyclodextrin.
  • solubility-enhancing agents include niacin and niacinamide.
  • the term “stable” refers to physical, rather than chemical, stability.
  • the metronidazole solutions of the invention are physically stable, that is substantially no crystal or precipitate from solution, when stored at refrigerated temperatures of 5°C for at least 7 days.
  • aqueous solutions of metronidazole at concentrations greater than 0.75% are obtained without the substantial presence of water-miscible organic solvents, such as ethyl alcohol or propylene glycol, which may be irritating to intact or damaged skin or mucosal surfaces.
  • organic solvents such as ethyl alcohol or propylene glycol
  • the elimination of these organic solvents provides a therapeutic solution that has decreased potential for irritation and makes the solutions especially good for treating topical dermatologic conditions, such as rosacea, that may be worsened by irritating chemicals present in a therapeutic formulation.
  • such organic solvents may be included in the solution, up to a concentration of about 10%.
  • the aqueous solutions are substantially free of organic solvents for MTZ.
  • the stable aqueous MTZ solutions of the invention have a concentration of MTZ greater than 0.75% w/w.
  • concentration of MTZ in the solution of the invention is about 1.0%.
  • concentration of MTZ in aqueous solution may be even higher, such as 1.25%, 1.5%, 2.0%, or 2.5%, or more.
  • the aqueous solution may be effectively used therapeutically as a topical formulation.
  • the solution is preferably in the form of a gel. Therefore, the aqueous MTZ solution preferably contains a gelling agent.
  • a gelling agent Any gelling agent that is water-dispersible and forms an aqueous gel of substantially uniform consistency is suitable for use in the solution of the invention so long as the gelling agent does not substantially interfere with the water solubility of MTZ or with the therapeutic efficacy of the solution. "Substantially interfere” means that the inclusion of the gelling agent decreases the solubility of MTZ to 0.75% w/w or less in aqueous solution.
  • a preferred gelling agent is hydroxyethylcellulose (NATROSOLTM, Hercules Inc., Wilmington, DE, USA).
  • suitable gelling agents include carboxyvinyl polymers, such as CARBOPOL ® 934, 940, and 941 (Noveon, Inc., Akron, OH, USA).
  • the level of the cyclodextrin in the solution may be varied depending upon the desired dissolved concentration of MTZ. In general, it is preferable to use as low a concentration of cyclodextrin as possible to obtain the desired concentration of MTZ because cyclodextrins are expensive, of limited aqueous solubility, not entirely free of toxicity, and the presence of cyclodextrin may be irritating to certain intact and diseased skin and mucosal surfaces.
  • the concentration of cyclodextrin in aqueous solution may be between 0.1% and 20%, or higher.
  • the concentration of cyclodextrin in the solution is no more than about 5% w/w.
  • beta-cyclodextrin the concentration in aqueous solution is limited by its solubility in water.
  • An aqueous solution, such as a gel, of beta-cyclodextrin is saturated at a concentration of about 0.5% at 5°C (refrigerator temperature).
  • the solutions, especially in gel formulation, are non-tacky, fast-drying, and cosmetically elegant.
  • the solutions, including the gel formulations are physically stable at 5°C (refrigerator temperature) or room temperature conditions for at least 7 days. No crystal formation or precipitation is observed after one week at 5°C.
  • the aqueous solution of the invention be substantially free of pharmacologically active compounds other than MTZ having a water-solubility which is increased by the presence of cyclodextrins.
  • These other compounds may act as competitors for the sequestration sites within the cyclodextrin cage structure and reduce the MTZ solubility enhancement by the cyclodextrin.
  • Multiple solutes that are increased in solubility by cyclodextrins may be utilized in the solutions so long as the level of cyclodextrin and the second solubility enhancer in the solution is sufficiently high to result in the desired dissolved concentration of MTZ, even in the presence of the competitor solute.
  • the amount of cyclodextrin in the solution is at a level below that which enhances the solubilization of MTZ to the level desired, and a second solubility enhancer, such as niacinamide or niacin, is included in the solution at a level that permits the desired concentration of MTZ in aqueous solution to be attained.
  • a second solubility enhancer such as niacinamide or niacin
  • the amount of niacinamide to be combined in the solution is less than that which, without the presence of BCD in the solution, can enhance the solubility of MTZ sufficiently to obtain a 1% solution of MTZ, or whatever level of MTZ is desired.
  • the concentration of BCD % w/w in the solution is preferably at a level of 1.0% or less and the concentration of niacinamide or niacin equal to or more than that of BCD.
  • aqueous solutions including the aqueous gels, of the invention may be made in any way that results in a stable MTZ concentration of greater than 0.75%, preferably of 1.0% or higher.
  • the solubility enhancers and the MTZ are combined in water, or a water-based solution, before the addition of a gelling agent, or at least before gelling of the solution occurs.
  • the solubility enhancers are dissolved in water before addition of the MTZ.
  • an aqueous solution of BCD and niacinamide or niacin is prepared, wherein the levels of BCD and niacinamide or niacin are as described above.
  • Metronidazole is then added to the solution.
  • the amount of metronidazole added to the solution may be an amount calculated to provide the desired concentration of MTZ or it may be an excess amount of MTZ.
  • the solution is preferably stirred or agitated at an elevated temperature and then permitted to cool to room or refrigerator temperature.
  • a gelling agent, if desired, is preferably added at any time after the addition of MTZ to the solution. Most preferably, the gelling agent is added to the solution after the agitation of the solution, during the cooling of the solution, or following cooling of the solution.
  • the solutions of the invention may be used for the topical treatment of dermatologic or mucosal disorders that are responsive to therapy with metronidazole.
  • a stable aqueous solution containing metronidazole at a concentration higher than 0.75% w/w, preferably about 1% or higher is topically applied to skin or mucosal surfaces in need of such therapy.
  • the applied solution preferably contains a cyclodextrin like BCD, as described above, in combination with niacin or niacinamide, as described above.
  • the therapeutic method of the invention may be used to treat any disorder that is responsive, or potentially responsive, to metronidazole therapy.
  • disorders that are suitably treated in accordance with the invention include inflammatory lesions on the skin, oral mucosa, or vaginal mucosa, diabetic foot ulcers, and certain infectious diseases that may be treated topically.
  • the method of the invention is used to treat rosacea.
  • the application of the metronidazole solution is preferably only once daily.
  • the solution is applied on a daily basis, one or more times per day, for a time sufficient to produce an amelioration or a cure of the disorder.
  • the solution may be applied one or more times daily for a prolonged period to prevent worsening of the disorder.
  • a kit for the topical treatment of skin or mucosal disorders.
  • the kit contains a jar 101 or other container suitable for holding an aqueous metronidazole solution as described herein, and instructions (not illustrated) for applying the solution topically to affected areas of the skin or mucosal surface.
  • the metronidazole solution has a concentration of metronidazole of about 1% or higher and the instructions call for applying the metronidazole solution to affected areas once daily.
  • the jar 101 is preferably packaged within a box 102, upon which additional information, such as instructions, may be written.
  • cyclodextrin may be used, such as beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin.
  • the second solubility enhancing agent may be a multiplicity of solubility enhancing agents, such as both niacin and niacinamide. It is intended that such modifications are included within the scope of the following claims.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Molecular Biology (AREA)
  • Polymers & Plastics (AREA)
  • Dermatology (AREA)
  • Dispersion Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Nanotechnology (AREA)
  • Biotechnology (AREA)
  • Medical Informatics (AREA)
  • Materials Engineering (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
EP02778822A 2001-12-24 2002-11-07 Aqueous compositions containing metronidazole Expired - Lifetime EP1467744B1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP10170958A EP2238980A1 (en) 2001-12-24 2002-11-07 Aqueous compositions containing metronidazole
EP10170977A EP2241320A1 (en) 2001-12-24 2002-11-07 Aqueous compositions containing metronidazole
CY20101101017T CY1111095T1 (el) 2001-12-24 2010-11-11 Υδατοδεις συνθεσεις που περιεχουν μετρονιδαζολη

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US33835 2001-12-24
US10/033,835 US6881726B2 (en) 2001-12-24 2001-12-24 Aqueous compositions containing metronidazole
PCT/US2002/036063 WO2003057135A2 (en) 2001-12-24 2002-11-07 Aqueous compositions containing metronidazole

Related Child Applications (2)

Application Number Title Priority Date Filing Date
EP10170977.2 Division-Into 2010-07-27
EP10170958.2 Division-Into 2010-07-27

Publications (3)

Publication Number Publication Date
EP1467744A2 EP1467744A2 (en) 2004-10-20
EP1467744A4 EP1467744A4 (en) 2006-07-05
EP1467744B1 true EP1467744B1 (en) 2010-09-15

Family

ID=21872727

Family Applications (3)

Application Number Title Priority Date Filing Date
EP02778822A Expired - Lifetime EP1467744B1 (en) 2001-12-24 2002-11-07 Aqueous compositions containing metronidazole
EP10170958A Ceased EP2238980A1 (en) 2001-12-24 2002-11-07 Aqueous compositions containing metronidazole
EP10170977A Withdrawn EP2241320A1 (en) 2001-12-24 2002-11-07 Aqueous compositions containing metronidazole

Family Applications After (2)

Application Number Title Priority Date Filing Date
EP10170958A Ceased EP2238980A1 (en) 2001-12-24 2002-11-07 Aqueous compositions containing metronidazole
EP10170977A Withdrawn EP2241320A1 (en) 2001-12-24 2002-11-07 Aqueous compositions containing metronidazole

Country Status (19)

Country Link
US (4) US6881726B2 (enExample)
EP (3) EP1467744B1 (enExample)
JP (1) JP4611632B2 (enExample)
KR (1) KR100718858B1 (enExample)
CN (1) CN100411624C (enExample)
AR (1) AR037755A1 (enExample)
AT (1) ATE481105T1 (enExample)
AU (1) AU2002340458B2 (enExample)
BR (1) BRPI0215331B8 (enExample)
CA (1) CA2470492C (enExample)
CY (1) CY1111095T1 (enExample)
DE (1) DE60237710D1 (enExample)
DK (1) DK1467744T3 (enExample)
ES (1) ES2352656T3 (enExample)
MX (1) MXPA04006210A (enExample)
PT (1) PT1467744E (enExample)
RU (2) RU2284810C2 (enExample)
WO (1) WO2003057135A2 (enExample)
ZA (1) ZA200405059B (enExample)

Families Citing this family (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6468989B1 (en) * 2000-07-13 2002-10-22 Dow Pharmaceutical Sciences Gel compositions containing metronidazole
DE10306453A1 (de) * 2003-02-17 2004-08-26 Deutsche Telekom Ag Administrator
US7456207B2 (en) * 2003-09-25 2008-11-25 Teva Pharmaceuticals Usa, Inc. Vaginal pharmaceutical compositions and methods for preparing them
FR2866566A1 (fr) * 2004-02-20 2005-08-26 Galderma Res & Dev Utilisation d'un inhibiteur de la secretion d'il-5,il-6 et/ou il-10 pour le traitement de la rosacee
FR2887149B1 (fr) * 2005-06-17 2007-08-03 Galderma Sa Procede de solubilisation du metronidazole
US20060093675A1 (en) * 2004-10-29 2006-05-04 Mathew Ebmeier Intravaginal treatment of vaginal infections with metronidazole compositions
US9446226B2 (en) * 2005-12-07 2016-09-20 Ramot At Tel-Aviv University Ltd. Drug-delivering composite structures
US20100105638A1 (en) * 2007-03-12 2010-04-29 Kerstin Den-Braven Cosmetic compositions
US20080287514A1 (en) * 2007-05-14 2008-11-20 Jerry Zhang Topical compositions containing metronidazole
US20080287513A1 (en) * 2007-05-14 2008-11-20 Jerry Zhang Topical compositions containing metronidazole
US20080312304A1 (en) * 2007-06-13 2008-12-18 Jerry Zhang Topical compositions containing metronidazole
ES2439497T3 (es) * 2007-09-04 2014-01-23 Meiji Seika Pharma Co., Ltd. Preparación de una inyección, de una solución para inyección y de un kit de inyección
AR061947A1 (es) * 2008-01-08 2008-08-10 Oscar Belluscio Daniel Metodo para la obtencion del complejo gonadotrofina corionica humana (gch) / ciclodextrina administrable por via oral, producto obtenido con dicho metodo y uso clinico-terapeutico del complejo gonadotrofina corionica humana (gch) / ciclodextrina
US7893097B2 (en) * 2008-02-02 2011-02-22 Dow Pharmaceutical Sciences, Inc. Methods and compositions for increasing solubility of azole drug compounds that are poorly soluble in water
EP2303353B1 (en) * 2008-06-12 2018-01-10 Ramot at Tel-Aviv University Ltd. Drug-eluting medical devices
US8729108B2 (en) * 2008-06-17 2014-05-20 Christopher J Dannaker Waterborne topical compositions for the delivery of active ingredients such as azelaic acid
WO2010047831A1 (en) * 2008-10-23 2010-04-29 Nycomed Us Inc. Stable metronidazole gel formulations
EP2201930A1 (en) 2008-12-23 2010-06-30 Intendis GmbH Hydrogel composition for the treatment of dermatological disorders
AU2010237599A1 (en) * 2009-04-14 2011-12-08 Medortus (Uk) Ltd Gel compositions for administration of pharmaceutically active compounds
US20120171184A1 (en) 2010-12-31 2012-07-05 Lajos Szente Cellular hydration compositions
CN105903028B (zh) * 2010-12-31 2020-10-16 东塘实验室有限公司 含有环糊精的细胞水合组合物
EP2658578A1 (en) * 2010-12-31 2013-11-06 Eastpond Laboratories Limited Cellular hydration compositions containing cyclodextrins
JP5864615B2 (ja) 2011-01-25 2016-02-17 ザ プロクター アンド ギャンブルカンパニー リポソーム及びそれを含むパーソナルケア組成物
CA2840571C (en) * 2011-06-28 2020-03-24 Medicis Pharmaceutical Corporation High dosage mucoadhesive metronidazole aqueous-based gel formulations and their use to treat bacterial vaginosis
US9511144B2 (en) 2013-03-14 2016-12-06 The Proctor & Gamble Company Cosmetic compositions and methods providing enhanced penetration of skin care actives
EP2952208A1 (en) * 2014-06-04 2015-12-09 Universidade de Santiago de Compostela Hydroalcoholic system for nail treatment
WO2016022066A1 (en) 2014-08-04 2016-02-11 Jerry Tan Eye Surgery Pte Ltd Pharmaceutical compositions for demodex related blepharitis and eyelid crusting
JP2015044850A (ja) * 2014-11-07 2015-03-12 イーストポンド・ラボラトリーズ・リミテッド シクロデキストリンを含有する細胞水和組成物
US9492374B2 (en) * 2015-03-25 2016-11-15 Jose Rafael Salinas Andrade Composition and method for treatment of ulcers
DK3723739T3 (da) 2017-12-15 2024-06-17 Tarsus Pharmaceuticals Inc Isoxazolin-parasiticidformuleringer og deres anvendelse til behandling af blepharitis
US11198831B2 (en) 2019-01-31 2021-12-14 Kvi Llc Lubricant for a device
CN111840632A (zh) * 2019-04-25 2020-10-30 广东泰宝医疗科技股份有限公司 一种含止血微囊的液体敷料及其制备方法
WO2021246966A1 (en) * 2020-06-02 2021-12-09 National University Of Singapore Compositions, their uses in therapy and methods thereof

Family Cites Families (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4032645A (en) * 1975-06-19 1977-06-28 G. D. Searle & Co. Injectable metronidazole composition
US4267169A (en) * 1978-07-22 1981-05-12 Toko Yakuhin Kogyo Kabushiki Kaisha Novel preparation of clotrimazole
GB8330969D0 (en) * 1983-11-21 1983-12-29 Wellcome Found Promoting healing
DE3346123A1 (de) 1983-12-21 1985-06-27 Janssen Pharmaceutica, N.V., Beerse Pharmazeutische praeparate von in wasser schwerloeslichen oder instabilen arzneistoffen und verfahren zu ihrer herstellung
US4596795A (en) * 1984-04-25 1986-06-24 The United States Of America As Represented By The Secretary, Dept. Of Health & Human Services Administration of sex hormones in the form of hydrophilic cyclodextrin derivatives
US4727064A (en) 1984-04-25 1988-02-23 The United States Of America As Represented By The Department Of Health And Human Services Pharmaceutical preparations containing cyclodextrin derivatives
US4837378A (en) * 1986-01-15 1989-06-06 Curatek Pharmaceuticals, Inc. Topical metronidazole formulations and therapeutic uses thereof
US5002935A (en) * 1987-12-30 1991-03-26 University Of Florida Improvements in redox systems for brain-targeted drug delivery
US5536743A (en) 1988-01-15 1996-07-16 Curatek Pharmaceuticals Limited Partnership Intravaginal treatment of vaginal infections with buffered metronidazole compositions
EP0335545B2 (en) 1988-03-29 1998-09-23 University Of Florida Pharmaceutical formulations for parenteral use
US5997856A (en) 1988-10-05 1999-12-07 Chiron Corporation Method and compositions for solubilization and stabilization of polypeptides, especially proteins
RU2029548C1 (ru) * 1989-07-07 1995-02-27 Центр по химии лекарственных средств Антимикробное или радиосенсибилизирующее средство
US5376645A (en) 1990-01-23 1994-12-27 University Of Kansas Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof
KR0166088B1 (ko) 1990-01-23 1999-01-15 . 수용해도가 증가된 시클로덱스트린 유도체 및 이의 용도
TW200402B (enExample) 1990-08-13 1993-02-21 Senju Pharma Co
DE69232535D1 (de) * 1991-06-24 2002-05-08 Pacific Biomedical Res Inc In langzeitkultur gehaltene hormon-absondernde pankreatische zellen
US5747341A (en) * 1991-06-24 1998-05-05 Pacific Biomedical Research, Inc. Culture media having low osmolarity for establishing and maintaining hormone-secreting cells in long-term culture
US5472954A (en) * 1992-07-14 1995-12-05 Cyclops H.F. Cyclodextrin complexation
US5324718A (en) * 1992-07-14 1994-06-28 Thorsteinn Loftsson Cyclodextrin/drug complexation
US5646131A (en) * 1994-02-22 1997-07-08 The Arab Company For Drug Industries And Medical Applicances (Acdima) Method for solubilizing drugs using cyclodextrins and carboxylic acids
DE69533724T2 (de) * 1994-03-28 2005-10-27 The Trustees Of Columbia University In The City Of New York Zusammensetzung zum inaktivieren von reizstoffen in flüssigkeiten
FR2722098B1 (fr) * 1994-07-06 1996-08-23 Cird Galderma Nouveaux medicaments a base de metro-nidazole ou d'un melange synergetique de metronidazole et de clindamycine
US5874418A (en) * 1997-05-05 1999-02-23 Cydex, Inc. Sulfoalkyl ether cyclodextrin based solid pharmaceutical formulations and their use
EP1007049A1 (en) * 1997-08-27 2000-06-14 Hexal AG New pharmaceutical compositions of meloxicam with improved solubility and bioavailability
US6017516A (en) * 1997-10-31 2000-01-25 Lekar Pharma Limited Pharmaceutical dental formulation for topical application of metronidazole benzoate and chlorhexidine gluconate
US6183766B1 (en) * 1999-02-12 2001-02-06 The Procter & Gamble Company Skin sanitizing compositions
US6468989B1 (en) * 2000-07-13 2002-10-22 Dow Pharmaceutical Sciences Gel compositions containing metronidazole
CN1116038C (zh) * 2000-11-18 2003-07-30 雷文彬 一种治疗痤疮的外用药液

Also Published As

Publication number Publication date
BRPI0215331B8 (pt) 2021-05-25
DK1467744T3 (da) 2010-12-20
US20080154030A1 (en) 2008-06-26
AR037755A1 (es) 2004-12-01
ZA200405059B (en) 2005-09-28
AU2002340458B2 (en) 2007-01-04
JP4611632B2 (ja) 2011-01-12
CN1649603A (zh) 2005-08-03
CN100411624C (zh) 2008-08-20
CA2470492A1 (en) 2003-07-17
RU2284810C2 (ru) 2006-10-10
US20030119783A1 (en) 2003-06-26
EP1467744A2 (en) 2004-10-20
CA2470492C (en) 2010-02-23
AU2002340458A1 (en) 2003-07-24
DE60237710D1 (de) 2010-10-28
WO2003057135A2 (en) 2003-07-17
KR20040075911A (ko) 2004-08-30
EP2238980A1 (en) 2010-10-13
EP1467744A4 (en) 2006-07-05
JP2005532990A (ja) 2005-11-04
ES2352656T3 (es) 2011-02-22
US20050124578A1 (en) 2005-06-09
PT1467744E (pt) 2010-11-30
US20100048659A1 (en) 2010-02-25
EP2241320A1 (en) 2010-10-20
KR100718858B1 (ko) 2007-05-16
RU2004122696A (ru) 2005-03-20
BRPI0215331B1 (pt) 2015-07-28
US7348317B2 (en) 2008-03-25
RU2413501C2 (ru) 2011-03-10
HK1071514A1 (en) 2005-07-22
CY1111095T1 (el) 2015-06-11
RU2006116252A (ru) 2007-12-10
ATE481105T1 (de) 2010-10-15
MXPA04006210A (es) 2005-05-17
WO2003057135A3 (en) 2003-12-18
BR0215331A (pt) 2005-05-10
US6881726B2 (en) 2005-04-19

Similar Documents

Publication Publication Date Title
EP1467744B1 (en) Aqueous compositions containing metronidazole
EP1303541B1 (en) Compositions containing metronidazole
US8658678B2 (en) Methods and compositions for increasing solubility of azole drug compounds that are poorly soluble in water
US20100105750A1 (en) Stable metronidazole gel formulations
US20080312304A1 (en) Topical compositions containing metronidazole
HK1071514B (en) Aqueous compositions containing metronidazole
HK1144770A (en) Aqueous compositions containing metronidazole
HK1144771A (en) Aqueous compositions containing metronidazole
US20080287515A1 (en) Topical compositions containing metronidazole
US20080287514A1 (en) Topical compositions containing metronidazole
US20080287513A1 (en) Topical compositions containing metronidazole

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20040723

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LI LU MC NL PT SE SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO

RIN1 Information on inventor provided before grant (corrected)

Inventor name: DOW, GORDON, J.

Inventor name: CHANG, YUNIK

REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1071514

Country of ref document: HK

A4 Supplementary search report drawn up and despatched

Effective date: 20060607

17Q First examination report despatched

Effective date: 20060816

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LI LU MC NL PT SE SK TR

AX Request for extension of the european patent

Extension state: LT LV

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REF Corresponds to:

Ref document number: 60237710

Country of ref document: DE

Date of ref document: 20101028

Kind code of ref document: P

REG Reference to a national code

Ref country code: CH

Ref legal event code: NV

Representative=s name: ISLER & PEDRAZZINI AG

REG Reference to a national code

Ref country code: PT

Ref legal event code: SC4A

Free format text: AVAILABILITY OF NATIONAL TRANSLATION

Effective date: 20101122

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

REG Reference to a national code

Ref country code: NL

Ref legal event code: T3

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

REG Reference to a national code

Ref country code: GR

Ref legal event code: EP

Ref document number: 20100402763

Country of ref document: GR

REG Reference to a national code

Ref country code: HK

Ref legal event code: GR

Ref document number: 1071514

Country of ref document: HK

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Effective date: 20110210

REG Reference to a national code

Ref country code: SK

Ref legal event code: T3

Ref document number: E 8347

Country of ref document: SK

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20110616

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 60237710

Country of ref document: DE

Effective date: 20110616

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 14

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 15

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 16

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 17

REG Reference to a national code

Ref country code: DE

Ref legal event code: R082

Ref document number: 60237710

Country of ref document: DE

Representative=s name: BOEHMERT & BOEHMERT ANWALTSPARTNERSCHAFT MBB -, DE

Ref country code: DE

Ref legal event code: R081

Ref document number: 60237710

Country of ref document: DE

Owner name: BAUSCH HEALTH IRELAND LTD., IE

Free format text: FORMER OWNER: DOW PHARMACEUTICAL SCIENCES, PETALUMA, CALIF., US

REG Reference to a national code

Ref country code: GB

Ref legal event code: 732E

Free format text: REGISTERED BETWEEN 20190815 AND 20190821

REG Reference to a national code

Ref country code: ES

Ref legal event code: PC2A

Owner name: BAUSCH HEALTH IRELAND, LTD.

Effective date: 20191017

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BG

Payment date: 20200928

Year of fee payment: 19

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 20201015

Year of fee payment: 19

Ref country code: TR

Payment date: 20201103

Year of fee payment: 19

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: EE

Payment date: 20201015

Year of fee payment: 19

Ref country code: CH

Payment date: 20201015

Year of fee payment: 19

Ref country code: CY

Payment date: 20201014

Year of fee payment: 19

Ref country code: MC

Payment date: 20201027

Year of fee payment: 19

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 20211020

Year of fee payment: 20

Ref country code: PT

Payment date: 20211021

Year of fee payment: 20

Ref country code: SK

Payment date: 20211026

Year of fee payment: 20

Ref country code: CZ

Payment date: 20211026

Year of fee payment: 20

Ref country code: AT

Payment date: 20211022

Year of fee payment: 20

Ref country code: DE

Payment date: 20211020

Year of fee payment: 20

Ref country code: ES

Payment date: 20211201

Year of fee payment: 20

Ref country code: DK

Payment date: 20211020

Year of fee payment: 20

Ref country code: FI

Payment date: 20211018

Year of fee payment: 20

Ref country code: IE

Payment date: 20211022

Year of fee payment: 20

Ref country code: LU

Payment date: 20211020

Year of fee payment: 20

Ref country code: GB

Payment date: 20211020

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IT

Payment date: 20211025

Year of fee payment: 20

Ref country code: GR

Payment date: 20211022

Year of fee payment: 20

Ref country code: FR

Payment date: 20211020

Year of fee payment: 20

Ref country code: BE

Payment date: 20211020

Year of fee payment: 20

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20211130

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: NL

Ref legal event code: MM

Effective date: 20211201

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CY

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20211107

Ref country code: BG

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20220531

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20211201

REG Reference to a national code

Ref country code: DE

Ref legal event code: R071

Ref document number: 60237710

Country of ref document: DE

REG Reference to a national code

Ref country code: DK

Ref legal event code: EUP

Expiry date: 20221107

REG Reference to a national code

Ref country code: SK

Ref legal event code: MK4A

Ref document number: E 8347

Country of ref document: SK

Expiry date: 20221107

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20221125

REG Reference to a national code

Ref country code: GB

Ref legal event code: PE20

Expiry date: 20221106

REG Reference to a national code

Ref country code: BE

Ref legal event code: MK

Effective date: 20221107

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK07

Ref document number: 481105

Country of ref document: AT

Kind code of ref document: T

Effective date: 20221107

REG Reference to a national code

Ref country code: SE

Ref legal event code: EUG

REG Reference to a national code

Ref country code: IE

Ref legal event code: MK9A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SK

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20221107

Ref country code: PT

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20221116

Ref country code: IE

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20221107

Ref country code: GB

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20221106

Ref country code: ES

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20221108

Ref country code: CZ

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20221107

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20220630

Ref country code: EE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20211130

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20220630